Journal of Molecular Histology

, Volume 35, Issue 6, pp 545–553 | Cite as

RNA interference: The molecular immune system

  • Omar Bagasra
  • Kiley R. Prilliman


Introduction of double-stranded RNA (dsRNA) into cells expressing a homologous gene triggers RNA interference (RNAi), or RNA-based gene silencing (RBGS). The dsRNA degrades corresponding host mRNA into small interfering RNAs (siRNAs) by a protein complex containing Dicer. siRNAs in turn are incorporated into the RNA-induced silencing complex (RISC) that includes helicase, RecA, and exo- and endo-nucleases as well as other proteins. Following its assembly, the RISC guides the RNA degradation machinery to the target RNAs and cleaves the cognate target RNA in a sequence-specific, siRNA-dependent manner. RNAi has now been documented in a wide variety of organisms, including plants, fungi, flies, worms, and more recently, higher mammals. In eukaryotes, dsRNA directed against a range of viruses (i.e., HIV-1, RSV, HPV, poliovirus and others) and endogenous genes can induce sequence-specific inhibition of gene expression. In invertebrates, RNAi can be efficiently triggered by either long dsRNAs or 21- to 23-nt-long siRNAs. However, in jawed vertebrates, dsRNA longer than 30 bp can induce interferon and thus trigger undesirable side effects instead of initiating RNAi. siRNAs have been shown to act as potent inducers of RNAi in cultured mammalian cells. Many investigators have suggested that siRNAs may have evolved as a normal defense against endogenous and exogenous transposons and retroelements. Through a combination of genetic and biochemical approaches, some of the mechanisms underlying RNAi have been described. Recent data in C. elegans shows that two homologs of siRNAs, microRNAs (miRNAs) and tiny noncoding RNAs (tncRNAs) are endogenously expressed. However, many aspects of RNAi-induced gene silencing, including its origins and the selective pressures which maintain it, remain undefined. Its evolutionary history may pass through the more primitive immune functions of prokaryotes involving restriction enzymes that degrade plasmid DNA molecules that enter bacterial cells. RNAi has evolved further among eukaryotes, in which its wide distribution suggests early origins. RNAi seems to be involved in a variety of regulatory and immune functions that may differ among various kingdoms and phyla. We present here proposed mechanisms by which RBGS protects the host against endogenous and exogenous transposons and retroelements. The potential for therapeutic application of RBGS technology in treating viral infections such as HIV is also discussed.


Gene Silence Noncoding RNAs Undesirable Side Effect Normal Defense Early Origin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams KL, Qiu YL, Stoutemyer M, Palmer JD (2002)Punctuated evolution of mitochondrial gene content:high and variable rates of mitochondrial gene loss and transfer to the nucleus during angiosperm evolution.Proc Natl Acad Sci 99:9905-9912.CrossRefPubMedGoogle Scholar
  2. Apetrei C, Robertson DL, Marx PA (2004)The history of SIVS and AIDS:epidemiology,phylogeny and biology of isolates from natu-rally SIV infected non-human primates (NHP)in Africa.Front Biosci 9:225-254.PubMedGoogle Scholar
  3. Ambros V (2001)MicroRNAs:tiny regulators with great potential. Cell 107:823-826.CrossRefPubMedGoogle Scholar
  4. Ambros V, Lee RC, Lavanway A, Williams PT, Jewell D (2003) Micro RNAs and Other Tiny Endogenous RNAs in C.elegans. Curr Biol 13:807-818.CrossRefPubMedGoogle Scholar
  5. Bagasra O (1999)In HIV and Molecular Immunity:Prospect for AIDS Vaccine.Eaton publishing, Natick,MA pp.22-28.Google Scholar
  6. Bagasra O, Amjad M (1997)Natural immunity against HIV-1:Pros-pect for AIDS vaccine.Front Biosci 2:387-402.Google Scholar
  7. Bagasra O, Amjad M (2000)Protection against Retroviruses are owing to a di.erent form of immunity:A RNA-Based Molecular Immunity hypothesis.Appl Immunochem Mol Morphol 8:133-146.CrossRefGoogle Scholar
  8. Bagasra O, Pomerantz RJ, Whittle P (1993)The role of CD8+lym-phocytes on unstimulated peripheral blood lymphocytes to infec-tion with HIV-1.Immunol Letters 35:83-92.CrossRefGoogle Scholar
  9. Bass BL (2000)Double-stranded RNA as a template for gene silenc-ing.Cell 101:235-238.CrossRefPubMedGoogle Scholar
  10. Baur A, Schwarz N, Ellinger S, Korn K, Harrer T, Mang K, Jahn G (1989)Continuous clearance of HIV in a vertically infected child.Lan 2:1045.CrossRefGoogle Scholar
  11. Beattie T, Rowland-Jones S, Kaul R (2002)HIV-1 and AIDS:what are protective immune responses?J HIV Ther 7:35-39.PubMedGoogle Scholar
  12. Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, Mills AA, Elledge SJ, Anderson KV, Hannon GJ (2003) Dicer is essential for mouse development.Nat Genet.35:215-217.CrossRefPubMedGoogle Scholar
  13. Boden D, Pusch O, Lee F, Tucker L, Ramratnam B (2003)Human immunode ciency virus type 1 escape from RNA interference.J Virol 77:11531-11535.CrossRefPubMedGoogle Scholar
  14. Bryson YJ, Pang S, Wei LS, Dickover R, Diagne A, Chen IS (1995) Clearance of HIV infection in a perinatally infected infant.New Engl J 332:833-838.CrossRefGoogle Scholar
  15. Carrington JC, Ambros V (2003)Role of microRNAs in plant and animal development.Science 301:336-338.CrossRefPubMedGoogle Scholar
  16. de Groot NG, Otting N, Doxiadis GG, Balla-Jhagjhoorsingh SS, Heeney JL, van Rood JJ, Gagneux P, Bontrop RE (2002)Evi-dence for an ancient selective sweep in the MHC class I gene rep-ertoire of chimpanzees.Proc Natl Acad Sci USA 99:11748-11753.CrossRefPubMedGoogle Scholar
  17. Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chateld C (1995)Genomic structure of an attenuated quasispecies of HIV-1 from a blood transfusion donor and recipients.Sci 270:988-991.Google Scholar
  18. Desset S, Meignin C, Dastugue B, Vaury C (2003)COM a Hetero-chromatic Locus Governing the Control of Independent Endoge-nous Retroviruses From Drosophila melanogaster.Genet 164: 501-509.Google Scholar
  19. Donze O, Picard D (2002)RNA interference in mammalian cells using siRNAs synthesized with T7 RNA polymerase.Nucleic Acids Res 30:e46.CrossRefPubMedGoogle Scholar
  20. Fire A (1999)RNA-triggered gene silencing.Trends Genet 15:358-363.CrossRefPubMedGoogle Scholar
  21. Gitlin L, Andino R (2003)Nucleic acid-based immune system:the antiviral potential of mammalian RNA silencing.J Virol 77:7159-7165.CrossRefPubMedGoogle Scholar
  22. Grishok A, Mello CC (2002)RNAi (Nematodes:Caenorhabditis ele-gans).Adv Genet 46:339-360.PubMedGoogle Scholar
  23. Hamilton AJ, Baulcombe DC (1999)A species of small antisense RNA in posttranscriptional gene silencing in plants.Sci.286:950-952.CrossRefGoogle Scholar
  24. Hannon GJ (2002)RNA interference.Nat 418:244-251.CrossRefPubMedGoogle Scholar
  25. Hirochika H, Okamoto H, Kakutani T (2000)Silencing of retro-transposons in Arabidopsis and reactivation by the ddm1 muta-tion.Plant Cell 12:357-369.CrossRefPubMedGoogle Scholar
  26. Hohjoh H (2002)RNA interference (RNAi)induction with various types of synthetic oligonucleotide duplexes in cultured human cells.FEBS Lett 521:195-199.CrossRefPubMedGoogle Scholar
  27. Hu WY, Myers CP, Kilzer JM, Pfaff SL, Bushman FD (2002)Inhi-bition of retroviral pathogenesis by RNA interference.Curr Biol 12:1301-1311.CrossRefPubMedGoogle Scholar
  28. Hull R, Harper G, Lockhart B (2000)Viral sequences integrated into plant genomes.Trends Plant Sci 5:362-265.CrossRefPubMedGoogle Scholar
  29. Hutvagner G, Zamore PD (2002)RNAi:nature abhors a double-strand.Curr Opin Genet Dev 12:225-232.CrossRefPubMedGoogle Scholar
  30. Jacque JM, Triques K, Stevenson M (2002)Modulation of HIV-1 replication by RNA interference.Nat 418:435-438.CrossRefGoogle Scholar
  31. Jakowitsch J, Mette MF, van Der Winden J, Matzke MA, Matzke AJ (1999)Integrated pararetroviral sequences de ne a unique class of dispersed repetitive DNA in plants.Proc Natl Acad Sci 96:13241-13246.CrossRefPubMedGoogle Scholar
  32. Jensen S, Gassama MP, Dramard X, Heidmann T (2002)Regulation of I-transposon activity in Drosophila:evidence for cosuppression of nonhomologous transgenes and possible role of ancestral I-related pericentromeric elements.Genet 162:1197-1209.Google Scholar
  33. Jeong Br BR, Wu-Scharf D, Zhang C, Cerutti H (2002)Suppressors of transcriptional transgenic silencing in Chlamydomonas are sen-sitive to DNA-damaging agents and reactivate transposable elements.Proc Natl Acad Sci 99:1076-1081.CrossRefPubMedGoogle Scholar
  34. Joost Haasnoot PC, Cupac D, Berkhout B (2003)Inhibition of virus replication by RNA interference.J Biomed Sci 10:607-616.CrossRefPubMedGoogle Scholar
  35. Kaul R, Plummer FA, Kimani J, Dong T, Kiama P, Rostron T, Njagi E, MacDonald KS, Bwayo JJ, McMichael AJ, Rowland-Jones SL (2000)HIV-1-Speci c Mucosal CD8+Lymphocyte Responses in the Cervix of HIV-1-Resistant Prostitutes in Nairobi. J Immunol 164:1602-1611.PubMedGoogle Scholar
  36. Ketting RF, Haverkamp TH, van Luenen HG, Plasterk RH (1999) Mut-7 of C.elegans,required for transposon silencing and RNA interference,is a homolog of Werner syndrome helicase and RNaseD.Cell 99:133-141.CrossRefPubMedGoogle Scholar
  37. Kulkarni PS, Butera ST, Duerr AC (2003)Resistance to HIV-1 infection:lessons learned from studies of highly exposed persis-tently seronegative (HEPS)individuals.AIDS Rev 5:87-103.PubMedGoogle Scholar
  38. Leirdal M, Sioud M (2002)Gene silencing in mammalian cells by preformed small RNA duplexes.Biochem Biophys Res Common 295:744-748.CrossRefGoogle Scholar
  39. Lindenbach BD, Rice CM (2002)RNAi targeting an animal virus: news from the front.Mol Cell 9:925-927.CrossRefPubMedGoogle Scholar
  40. Mallory AC, Ely L, Smith TH, Marathe R, Anandalakshmi R, Fagard M, Vaucheret H, Pruss G, Bowman L, Vance VB (2001) HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal.Plant Cell 13:571-583.CrossRefPubMedGoogle Scholar
  41. Marin L, Lehmann M, Nouaud D, Izaabel H, Anxolabehere D, Ronsseray S (2000)P-Element repression in Drosophila melanog-aster by a naturally occurring defective telomeric P copy.Genetics 155:1841-1854PubMedGoogle Scholar
  42. Martin G (2002)V(D)J Recombination:RAG proteins,repair factors,and regulation.Annu Rev Biochem 71:101-132.CrossRefPubMedGoogle Scholar
  43. McClintock B (1950)The origin and behavious of mutable loci in maize.Proc Natl Acad Sci 36:347.Google Scholar
  44. Messele T, Rinke de Wit TF, Brouwer M, Aklilu M, Birru T, Fontanet AL, Schuitemaker H, Hamann D (2001)No di.erence in in vitro susceptibility to HIV type 1 between high-risk HIV-negative Ethiopian commercial sex workers and low-risk control subjects. AIDS Res Hum Retroviruses.17:433-441.CrossRefPubMedGoogle Scholar
  45. Miyagishi M, Taira K (2002)U6 promoter driven siRNAs with four uridine 3 ′overhangs e.ciently suppress targeted gene expression in mammalian cells.Nat Biotechnol 20:497-500.CrossRefPubMedGoogle Scholar
  46. Muchmore EA (2001)Chimpanzee models for human disease and immunobiology.Immunol Rev 183:86-93.CrossRefPubMedGoogle Scholar
  47. Nakayashiki H, Ikeda K, Hashimoto Y, Tosa Y, Mayama S (2001) Methylation is not the main force repressing the retrotransposon MAGGY in Magnaporthe grisea.Nucleic Acids Res 29: 1278-1284.CrossRefPubMedGoogle Scholar
  48. Ondoa P, Kestens L, Davis D, Vereecken C, Willems B, Fransen K, Vingerhoets J, Zissis G, ten Haaft P, Heeney J, van der Groen G (2001)Longitudinal comparison of virus load parameters and CD8 T-cell suppressive capacity in two SIVcpz-infected chimpan-zees.J Med Primatol 30:243-253.CrossRefPubMedGoogle Scholar
  49. Ostertag EM, Kazazian HH Jr (2001)Biology of mammalian L1 retrotransposons.Annu Rev Genet 35:501-538.CrossRefPubMedGoogle Scholar
  50. Otting N, de Groot NG, Doxiadis GG, Bontrop RE (2002)Exten-sive Mhc-DQB variation in humans and non-human primate spe-cies.Immunogenetics 54:230-239.CrossRefPubMedGoogle Scholar
  51. Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS (2002)Short hairpin RNAs shRNAs)induce sequence-speci c silencing in mammalian cells.Genes Dev 16:948-958.CrossRefPubMedGoogle Scholar
  52. Paul CP, Good PD, Winer I, Engelke DR (2002)Eective expression of small interfering RNA in human cells.Nat Biotechnol 20: 505-508.CrossRefPubMedGoogle Scholar
  53. Paxton WA, Martin SR, Tse D, O'Brien TR, Skurnick J, VanDe-vanter NL, Padian N, Braun JF, Kotler DP, Wolinsky SM, Koup RA (1996)Relative resistance to HIV-1 infection of CD4 lympho-cytes from person who remain uninfected despite multiple high-risk sexual exposure.Nat Med 2:412-417.CrossRefPubMedGoogle Scholar
  54. Robertson DL, Sharp PM, McCutchan FE, Hahn,BH (1995) Recombination in HIV-1.Nat 374:124-126.CrossRefGoogle Scholar
  55. Robin S, Chambeyron S, Bucheton A, Busseau I (2003)Gene silenc-ing triggered by non-LTR retrotransposons in the female germline of Drosophila melanogaster.Genet 164:521-531.Google Scholar
  56. Roques PA, Gras G, Parnet-Mathieu F, Mabondzo AM, Dollfus C, Narwa R, Marce D, Tranchot-Diallo J, Herve F, Lasfargues G (1995)Clearance of HIV infection in 12 perinatally infected children: clinical,virological and immunological data.AIDS 9:F19-F26.PubMedGoogle Scholar
  57. Salemi M, Oliveira T.De, Courgnaud T, Moulton V, Holland B, Cassol S, Switzer WM, Vandamme AM (2003)Mosaic Genomes of the Six Major Primate Lentivirus Lineages Revealed by Phylo-genetic Analyses.J Virol 77:7202-7213.CrossRefPubMedGoogle Scholar
  58. Salo E, Baguna J (2002)Regeneration in planarians and other worms:new ndings,new tools,and new perspectives.J Exp Zool 292:528-539.CrossRefPubMedGoogle Scholar
  59. Seitz H, Youngson N, Lin SP, Dalbert S, Paulsen M, Bachellerie JP, Ferguson-Smith AC, Cavaille J (2003)Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene.Nat Genet 34:261-262.CrossRefPubMedGoogle Scholar
  60. Sharp PM, Bailes E, Robertson DL, Gao F, Hahn BH (2000) Origins and evolution of AIDS viruses.Biol Bull 196:338-342.Google Scholar
  61. Sharp PA (1999)RNAi and double-strand RNA.Genes Dev 15: 139-141.Google Scholar
  62. Sui G, Soohoo C, Aarel B, Gay F, Shi Y, Forrester WC, Shi Y (2002)A DNA vector-based RNAi technology to suppress gene expression in mammalian cells.Proc Natl Acad Sci 99:5515-5520.CrossRefPubMedGoogle Scholar
  63. Tabara H, Sarkissian M, Kelly WG, Fleenor J, Grishok A, Timmons L, Fire A, Mello CC (1999)The rde-1 gene,RNA interference, and transposon silencing in C.elegans.Cell 99:123-132.CrossRefPubMedGoogle Scholar
  64. Tuschl T (1999)Targeted mRNA degradation by double-stranded RNA in vitro.Genes Dev 13:3191-3197.CrossRefPubMedGoogle Scholar
  65. Urwin PE, Lilley CJ, Atkinson HJ (2002)Ingestion of double-stranded RNA by preparasitic juvenile cyst nematodes leads to RNA interference.Mol Plant Microbe Interact 15:747-752.PubMedGoogle Scholar
  66. Yu JY, DeRuiter SL, Turner DL (2002)RNA interference by expression of short-interfering RNAs and hairpin RNAs in mam-malian cells.Proc Natl Acad Sci 99:6047-6052.CrossRefPubMedGoogle Scholar
  67. Zamore PD, Tuschl T, Sharp PA, Bartel DP (2000)RNAi:double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21-23 nucleotide intervals.Cell 101:25-33.CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Omar Bagasra
    • 1
  • Kiley R. Prilliman
    • 2
  1. 1.South Carolina Center for BiotechnologyClaflin UniversityOrangeburgUSA
  2. 2.Baylor Institute for Immunology ResearchDallasUSA

Personalised recommendations